Choroid plexus tumors: A spectrum from benign to malignant

Choroid plexus tumors (CPT) are believed to originate from outgrowths of the choroid plexus. Despite their broad spectrum of symptoms, invasive nature, and prognosis, most CPTs typically exhibit similar presentations due to their relationship with the cerebral ventricles, as well as the mechanical obstruction and mass effect associated with their growth. In addition, these tumors mainly affect the pediatric population, further complicating the differentiation between benign and malignant subtypes. The World Health Organization classifies CPTs into three grades, namely, grades I, II, or III, based on their mitotic activity, which determine the benign or malignant nature of the tumors. CPTs classified by the World Health Organization (WHO) include choroid plexus papillomas (CPP), atypical CPPs (aCPP), and malignant choroid plexus carcinomas (CPC). Choroid plexus adenomas represent an additional category of benign CPTs not officially classified by the WHO. Despite the variations in histology, immunohistochemistry, imaging, treatment, and prognosis, CPTs cannot be reliably distinguished based solely on clinical presentation. Therefore, in this review, we aim to provide a comprehensive overview of each tumor subtype, along with the current management approach and emerging treatments.


Introduction
Choroid plexus tumors (CPT) encompass a spectrum of severity, ranging from asymptomatic and benign cases to highly aggressive and malignant cancers.They constitute approximately This is an Open Access article distributed under the terms of the Creative Commons Attribution License, permitting distribution, and reproduction in any medium, which provided that the original work is properly cited.
1 -4% of childhood brain tumors and are commonly observed within the 1 st year of life, accounting for up to 20% of brain tumors in children under the age of 1 year old [1,2] .CPTs are graded from 1 to 3 as benign choroid plexus papilloma (CPP), atypical CPP (aCPP), and malignant choroid plexus carcinoma (CPC), respectively.In addition, rare cases of choroid plexus adenomas (CPA) have been reported, usually as incidental findings.Benign, grade I tumors in the fourth ventricle and cerebellopontine angle are commonly observed in adults [3] .In addition, CPTs in the cerebellopontine angle are more benign than those located in the fourth ventricle [3] .In contrast, malignant, grade III tumors in the supratentorium are more prevalent in pediatric populations [4] .The 5-year survival rates for CPT patients vary, ranging from 81% in those diagnosed with CPP to 41% in patients with CPC [3] .Poor prognosis in CPTs is associated with age >40 or <10 [3] .
CPTs are often asymptomatic and typically manifest clinically only after significant tumor growth and malignancy development.CPTs can cause mechanical obstruction of cerebrospinal fluid (CSF) flow, blockage of arachnoid granulation due to tumor hemorrhage, and overproduction of CSF, resulting in hydrocephalus and subsequent symptoms such as headache, diplopia, and ataxia [5] .Commonly used, yet non-specific, biomarkers for CPT diagnosis include transthyretin, glial fibrillary acidic protein (GFAP), epithelial membrane antigen, and synaptophysin [6] .Lateral ventricle CPP, one of the more common types of CPTs, often appears as a hypertrophied anterior choroidal artery on imaging.In addition, symmetrical hydrocephalus observed on imaging may also aid in the diagnosis of CPTs [7] .
An early intervention involving tumor resection, coupled with adjuvant treatments such as chemotherapy or radiotherapy, is the standard of care for CPTs, as metastasis is associated with poor outcomes.Ventriculoperitoneal (VP) shunts are beneficial both pre-and postoperatively to prevent cerebellar tonsil herniation and address acute hydrocephalus.The exact treatment approach varies depending on tumor grade, size, and location.However, surgical resection combined with adjuvant treatment remains crucial for attaining optimal outcomes [8] .Tumor relapse is associated with worse outcomes, particularly in patients with CPC [3] .This review focuses on novel approaches for diagnosing and treating CPTs.In addition, differences between benign and malignant CPTs and their locations will be explored to further explain variations in treatment approaches.This study will provide a comprehensive presentation by delving into differences in pathophysiology, prevalence, treatment, and prognosis of benign and malignant CPTs.

Choroid plexus papilloma
CPPs are benign neoplasms of the central nervous system with a neuroepithelial origin, proposed to represent hamartomatous overgrowths [25] .These rare tumors are most commonly present in the first 10 years of life [26] .CPPs account for <1% of brain tumors in adults, 2.3% of primary intracranial tumors in children, and 3.9% of cerebral neoplasms in infants [22,24,27,28] .The previous studies have demonstrated associations between the occurrence of CPTs and the BK virus, the John Cunningham (JC) virus, and the Simian virus (SV) 40 [29,30] .Other studies have found associations with tumor suppressor 53 (TP53) germline mutations, Pierpont syndrome, Aicardi syndrome, 9p duplication, and hypomelanosis [31][32][33][34] .For instance, one study identified the R248W mutation of the TP53 gene as a common defect in patients with CPTs [35] .Despite these associations, the etiology of CPPs remains unclear.
The WHO classifies CPPs as grade I CPTs with <2 mitotic figures per 10 high power fields (HPFs) [27,36] .Mitotic activity, necrosis, and nuclear pleomorphism are typically absent in microscopy.However, bland columnar epithelium can be observed lining papillary fronds [37] .Grossly, CPPs are pink, friable, soft, globular with irregular projections, and highly vascular.Immunohistochemistry analysis has revealed that CPPs are positive for cytokeratin, podoplanin, S-100, and vimentin [37,38] .CPPs may show positive expression for GFAP, with higher expressivity observed in patients above 20 years of age.Transthyretin follows a similar trend with higher expressivity in older patients with CPPs [9] .S-100 is more highly expressed in fourth ventricle tumors than lateral ventricle tumors.CPPs are most commonly found in the lateral ventricle, occurring in 50% of pediatric patients, and in the fourth ventricle, observed in 40% of adult patients [25] .Other reported that sites of occurrence include the brain stem, cerebellopontine angle, pineal region, posterior fossa, posterior third ventricle, sacral canal, and sellar region [25,[39][40][41][42][43][44] .
As a result of CPPs, arachnoid granulation is blocked due to CSF overproduction or hemorrhage.This direct mechanical obstruction of CSF causes hydrocephalus and associated clinical symptoms [8,45] .The clinical presentation can vary, ranging from headache, hemifacial spasm, or CSF rhinorrhea to hydrocephalus [45,46] .Due to the rapid growth observed in CPPs and the anatomy of the cerebral ventricular system, more severe symptoms requiring earlier intervention are found in CPPs located in the fourth ventricle [8,47] .
Prenatal ultrasound and neurosonogram through an unfused anterior fontanelle will demonstrate echogenic lesions with the bidirectional flow in the ventricles throughout diastole [48] .CT scans demonstrate ventriculomegaly with hyper-to isodense lobulated lesions and slightly irregular margins within the ventricles [49] .Calcifications can be observed in about 25% of patients.MRI demonstrates flow voids and enhanced well-defined intraventricular lesions.The masses are lobulated and frond-like, appearing hypointense and hyperintense on axial spin-echo T1-weighted images (T1WI) and axial fast spin-echo T2-weighted images (T2WI), respectively [50,51] .
Radiosurgery may be considered a possible treatment option, but the definitive treatment for CPPs is surgical resection, sometimes complemented with adjuvant chemotherapy [52,53] .However, the timing of surgery can vary based on the patient's presentation and symptoms [54] .In asymptomatic patients, treatment options include prompt removal, removal on radiographic changes on follow-up imaging, or removal when symptoms manifest.Tumor resection is easier in the setting of hydrocephalus, but waiting for the development of hydrocephalus can result in subarachnoid hemorrhage, seizures, cognitive defects, or mass effect-induced focal defects [52,54,55] .Pre-operative embolization and percutaneous stereotactic intratumoral embolization with a sclerosing agent are approaches used to reduce blood flow and optimize tumor resectability [56,57] .This is particularly important in pediatric patients, as blood loss is a leading contributor to the perioperative mortality rate (12%) during surgical resection of CPPs in the 1 st year of life [58] .However, surgical outcomes and cure rates approach 100% in infants and young children up to 4 years old [59] .Presurgical irradiation can also be used for growing residual CPPs, while chemotherapy can be used to prevent recurrence and improve survival [52] .Although recurrence is rare, cases of craniospinal seeding and suprasellar metastases have been reported [60] .
Post-operative complications include persistent features of hydrocephalus and increased intracranial pressure, resulting in a range of visual defects from papilledema and optic atrophy to visual loss.Other complications include cognitive defects, seizures, bleeding, and CSF rhinorrhea [54,[61][62][63].

Atypical choroid plexus papilloma
Atypical choroid plexus papillomas are an intermediate subtype of CPTs that demonstrate intermediate histology, specifically mitotic activity, between CPPs and CPCs [27,64] .The median age of diagnosis for aCPPs is between 8.4 and 12 months, although there are reports of aCPPs occurring in adults [59,[65][66][67][68] .Many aCPPs were misdiagnosed as either CPPs or CPCs before the WHO classified them into their own category in 2007.Consequently, the reported incidence was lower than that of CPPs and CPCs.
The WHO classifies aCPPs as grade II CPTs with 2 -5 mitotic figures per 10 HPFs [27,64] .Compared to CPP, aCPPs demonstrate necrosis, brisk mitotic activity, and increased cell density and nuclear pleomorphism [68] .These features contribute to early metastases observed in aCPPS, which pose 5 times increased risk of recurrence at 5 years [23] .Microscopy also reveals portions of papillary growth consisting of cuboidal to columnar cells [67] .Grossly, aCPPs are friable, soft, globular masses with irregular projections, and high vascularity [37,67] .Immunohistochemistry findings can vary from case to case.Atypical CPPs were positive for S-100, synuclein, and vimentin [68] .The lateral ventricle is the primary site of occurrence for aCPPs, with other less common locations including the third and fourth ventricle.In some cases, aCPPs have been reported in the cerebral hemispheres, unrelated to the ventricular system [66,68] .
The clinical symptoms associated with aCPPs are likely a result of the same pathophysiology observed in CPPs due to their similar morphology and behavior [8,45] .The clinical presentation is a combination of symptoms caused by hydrocephalus and increased intracranial pressure or neurological symptoms resulting from the mass effect.These symptoms include headache, gait disturbances, vertigo, diplopia, and paresis [66,68,69] .CT and MRI scan findings in aCPPs are similar to those seen in CPPs as well.However, MRI findings in aCPPs are more likely to show cysts, necrotic changes, peritumoral edema, unclear tumor boundaries, and larger volume masses.In addition, masses are isointense, hyperintense, and isointense on T1WI, T2WI, and diffusion-weighted images (DWI), respectively [48,49,68] .
Due to a lack of clinical and long-term follow-up data, a standard treatment approach for aCPPs has not been established [70] .The suggested approach is maximal surgical resection [66] , which often results in the resolution of hydrocephalus, resolution of symptoms associated with increased intracranial pressure, and a return to normal ventricular morphology in most cases.Hydrocephalus may persist in some cases even after treatment [68] .Chemotherapy courses with and without irradiation administered in cases of aCPPs with metastases and incomplete resection have demonstrated an 89% 5-year overall survival probability [66] .

Choroid plexus carcinomas
CPCs are a malignant neoplasm type of CPTs proposed to originate from epithelial progenitor cells of the choroid plexus [71] .CPCs share a similar incidence rate as CPTs, with approximately 20% occurring in the adult population and 80% occurring in the pediatric population [2,72] .Previous studies have found associations between CPCs and Li-Fraumeni syndrome, which carries TP53 germline mutations [34,73] .In addition, other studies have identified associations between CPCs and somatic TP53 mutations.Furthermore, spontaneous TP53 germline mutations have been linked to cases of CPCs [74] .
The pathophysiology of the clinical symptoms observed in CPCs is proposed to be similar to the previously discussed CPTs because of the mechanical obstruction and mass effect associated with the tumors and their relationship with cerebral ventricular anatomy [2,8,45,79] .Despite the malignant nature of CPCs, clinical presentation alone is not enough to distinguish them from other CPTs, as they all present with similar symptoms.The MRI findings of CPCs are highly variable, demonstrating masses that are iso-or hypointense, hyper-, hypo-, or isointense, and hypo-, iso-, hyper-, or mixed intensity on T1WI, T2WI, and DWI, respectively [68,69,71,75,76,82] .
The most effective proposed treatment for CPCs is a combination of surgical resection, radiotherapy, and chemotherapy.However, the order of treatment modality and the required amount of adjuvant treatment remain unclear and are debated in the literature [80,83] .Although surgical resection is the most important factor for long-term survival, resection alone is associated with poor outcomes due to the rapid progression of the disease [84] .Radiotherapy is considered an option for extending survival but can only be used in patients above the age of 3 who requires narrow radiation fields.Consequently, radiation therapy is an unlikely option in most cases, considering that CPCs typically occur at a young age and are often of significant size.However, patients below the age of 3 can receive adjuvant chemotherapy, which can contribute to long-term survival but cannot prevent CPC recurrence [3,80,83,84] .
CPCs carry a poor prognosis due to the challenges in achieving gross total resection, which is accomplished in only 40 -50% of cases, because of the invasiveness of the mass and the high risk of intraoperative hemorrhage [85][86][87] .Patients with CPCs have a median survival of 2.5 -3 years.Moreover, worse outcomes have been observed in patients identified with TP53 mutation using immunohistochemistry (Figure 1 and Table 1) [34,75,88] .

Emerging treatments and preclinical interventions
Emerging treatments for CPTs include advancements that supplement the conventional surgical intervention but may serve as standalone treatments in the future.Emerging treatments for CPTs can be categorized as neuroendoscopy, laser interstitial thermal therapy (LITT), photothermal therapy (PTT), immunotherapy, manipulation of the tumor microenvironment (TME), gene therapy, epigenetic modulators, and nanotechnology.

Neuroendoscopy
The use of endoscopy in neurosurgery, known as neuroendoscopy, allows for maximal resection in a minimally invasive manner without the need for brain retraction by utilizing the natural cavity of the ventricular system.This minimally invasive nature of the treatment and the inherent association CPTs have with the ventricular system make it an appealing technology for CPT resection.Limitations of this approach include large tumor size, dense vascularization, and inability to tolerate long surgical procedures [89] .Therefore, the indications for this type of surgery include small tumor size (<3 cm in diameter), lack of hard consistency, and poor vascularization [90] .As CPTs of the third ventricle tend to be smaller and less vascular than their counterparts in the lateral ventricle, most cases of pure endoscopic resection focused on tumors in this site, with some more recent exceptions [91] .
While neuroendoscopy has gained growing popularity in the context of choroid plexus coagulation, open microsurgical resection is still considered the standard treatment of CPT resection.Nevertheless, several purely endoscopic resections of CPTs have been attempted in the past, yielding promising results [92][93][94][95][96][97][98][99] .Some approaches, such as those reported by Reddy et al., involved a hybrid endoscopic and microsurgical approach to a third ventricle CPT [94] .In this case, endoscopy was used initially to biopsy and mobilizes the tumor from the third ventricle into the lateral ventricle, followed by open removal of resected tissue via a transcortical approach.Spennato et al. recently reported two cases of pure endoscopic removal of CPPs in the 3 rd ventricle: one in a 7-month-old infant with macrocrania and bulging fontanel, and another in a 3-year-old boy who underwent an MRI because of a month-long headache.In both cases, tumors were successfully resected, and MRI confirmed the absence of recurrence at the 3-year and 5-year follow-up, respectively.As these tumors have a higher incidence in infants and toddlers, who are more susceptible to surgical complications, neuroendoscopy may be the preferred method to minimize surgical trauma in this fragile population.The minimal surgical trauma associated with neuroendoscopy was the primary reason for adopting a monoportal neuroendoscopic approach in a 5-month-old male infant and a 10-week-old male infant, who might not have survived the trauma of open surgery [92,93] .
While these case reports focus on tumors that meet the size criteria for endoscopic resection, endoscopy can also be used for large tumors in a segmental removal approach, allowing smaller segments to pass through the scope port.Optical and electromagnetic neuronavigation may obviate the need for ventricular dilatation, which in the past was considered a prerequisite for ventricular neuroendoscopy.The use of modern neuroendoscopic tools, such as endoscopic ultrasonic surgical aspirators, may obviate some of these limitations in the future [90,100] .

LITT and PTT
LITT is a less invasive approach that uses laser energy to heat and destroy tumor cells.LITT is usually MRI-guided and particularly useful for tumors in difficult-to-reach areas, such as CPTs.Despite this, therapeutic application in growths of the choroid plexus has been very limited.While LITT has historically been indicated for recurrent glioblastoma, it has continued to see success in treating other brain tumors [101][102][103][104][105] .A case series by Tovar-Spinoza and Choi followed 11 pediatric patients with 12 brain tumors and reported successful ablations with minimal complications using LITT [106] .Although many of the lesions treated were located in difficult and risky areas to treat, such as the cerebellar peduncle, thalamus, or midbrain, only a single patient with 2 choroid plexus growths was treated.Based on these findings, while administration of LITT in the choroid plexus is possible, further pre-clinical trials using animal models are warranted to optimize the treatment of cancerous growths in this region.
PTT is another novel, non-invasive cancer treatment which has emerged in recent years [107,108] .Th is therapy uses photothermal agents that absorb light energy and convert it into thermal energy to induce heat ablation of tumor cells upon laser irradiation [109] .There are two general methods: traditional PTT (>50°C) and mild PTT (42 -45°C).Traditional PTT uses high heat to induce tumor necrosis but may result in inevitable damage and inflammation of surrounding tissue [110] .In contrast, mild PTT is a more promising technology for brain tumors because of its negligible side effects, inducing apoptosis rather than necrosis [111] .Furthermore, mild PTT offers the added advantages of loosening the dense structure in tumor tissues, enhancing blood perfusion, and alleviating the hypoxic microenvironment.These advantages can subsequently increase the infiltration of immune cells, improve the delivery of antitumor drugs, and boost the generation of reactive oxygen species, respectively [112][113][114][115][116] .While the use of PTT to treat CPTs is scarce, many studies have investigated its efficacy on other brain tumors, such as glioblastomas, with recent advances in nanotechnology further advancing its therapeutic potential [117,118] .Unlike gliomas, which have a higher incidence in more superficial structures of the brain, CPTs emerge deeper, posing a possible hurdle to be treated with PTT and LITT.Further studies should focus on developing methods to deliver these modalities to deeper structures of the brain, perhaps by means of intra-ventricular delivery [119] .

Immunotherapy and TME
In terms of success rates, the efficacy of conventional anticancer therapeutic approaches, such as chemotherapy, is limited by the non-specific toxicity and low specificity toward specific tumors [120] .Immunotherapy, on the other hand, is an emerging treatment option for cancer that leverages a patient's natural immunity or uses specific tumor biomarkers to avoid administering more broadly toxic chemotherapeutic agents.The predominant emerging forms of cancer immunotherapy to treat brain tumors include peptide-based vaccines, natural killer (NK) cell therapy, dendritic cell vaccines, immune checkpoint inhibitors, and chimeric antigen receptor T cell (CAR-T) therapy [121][122][123][124] .
Another promising avenue is the manipulation of the TME, focusing on therapies that target the surrounding cellular processes that cancerous cells utilize to sustain themselves and proliferate [125] .While current research on CPTs mainly focuses on their genetic and molecular characteristics, further investigation into their biomechanical mechanisms is warranted, as understanding these aspects may further assist the development of therapeutic and diagnostic techniques.

Peptide-based vaccines-Therapeutic cancer vaccines function by inducing systemic immunity against antigens overexpressed by tumor cells. Several studies have
shown that cancer vaccines are generally well tolerated in pediatric populations and provide preliminary evidence of immunological and modest clinical activity, albeit primarily on gliomas of varying grades [126][127][128] .However, therapeutic vaccines are only available through clinical trials and, as of the date of this review, ClinicalTrials.govlists 1,446 studies in the United States for the condition or disease of "Cancer," 56 studies for "Brain Cancer," and only 1 study for "Choroid Plexus Tumors" [129] .One notable study, NCT00014573, includes CPTs among other brain cancers studied using vaccine therapy as an adjuvant (partial resection of the tumor, followed by chemotherapy and vaccine therapy, followed by stem cell implantation with interleukin-2) [130] .Although cancer vaccines have shown promise in treating brain cancers such as CPTs, they have yet to achieve their full potential as standalone cancer therapies.This limitation could be attributed to factors including the choice of tumor antigen, immune tolerance mechanisms, and the development of an immunosuppressive TME [131] .However, advances in nanomedicine may offer solutions to combat these limitations [132][133][134][135][136][137] .

NK cell therapy and dendritic cell vaccines-Another set of immunotherapy approaches involves the use of NK cells and dendritic cells, both of which play key roles
in T-cell activation.NK cells are apt at recognizing tumors despite reduced or eliminated MHC-I expression and antigen presentation.They have an upstream recruitment role in type 1 dendritic cells and CD8+ T cells, thus promoting cancer immunity to overcome the oncoprotective TMEs that sustain and promote tumor growth and proliferation [138][139][140][141] .While most studies focus on glioblastomas, which are the most aggressive and malignant primary brain tumors in adults, these therapies may soon be applied to CPTs.NK cells are not only endogenously found in the choroid plexus but can also access the brain through the choroid plexus itself [124,142,143] .Similarly, while the use of dendritic cell vaccines has not explicitly been studied in the context of choroid plexus neoplasms, several approaches are being tested in order to exploit type 1 dendritic cells in anti-tumor immunotherapies of other CNS tumors with some modest success, opening the possibility for this technology to be applied in the near future for treating CPTs [144] .

Immune checkpoint therapy and adoptive T-cell transfer-Similar to
the above-mentioned treatments, the use of immune checkpoint modulators and adoptive T-cell transfers, such as CAR-T therapy, for CPTs is sparse despite the growing number of emerging treatments for other cancer types.However, ongoing investigations are exploring key anticancer immune checkpoint players [145,146] .At present, there are four clinical trials investigating immunotherapies against CPTs.Among these clinical trials, one phase 2 study evaluates the efficacy of immune checkpoint inhibitor (ICI) nivolumab, a monoclonal antibody targeting the programmed death-1 (PD-1) receptor expressed on the surface of activated human lymphocytes [147] .Another recent study focused on PD-1, utilizing functionalized biomimetic particles and combining the blockade approach with photothermal ablation to enhance immunotherapy (although the focus here was on colorectal cancer) [125] .
Adoptive T-cell therapy using CAR-T-cells is another promising approach for treating brain tumors.These CART-cells are engineered to target tumor-specific neoantigens, independent of major histone compatibility presentation of these antigens.There are three ongoing phase I clinical trials, all evaluating CAR-T-cell therapies delivered through an indwelling catheter into either the tumor resection cavity or ventricular system in pediatric and young adult patients.The trials involve EGFR806-specific, B7H3-specific, and HER2-specific, CAR CD4+ and CD8+ T cells [148][149][150] .In pre-clinical trials using murine models, several noteworthy adoptive T-cell transfer techniques with translational potential have been investigated.One of the techniques involves injecting T Ag-specific donor CD8+ T cells into transgenic mice expressing SV 40 oncogene after whole-body radiation administration.The use of the technique resulted in rapid, high-level T cell accumulation within the brain, elimination of CPC tumors, persistence of T cells at tumor sites, and prevention of tumor recurrence [151,152] .A study by Cozza et al. further demonstrated that intraperitoneal injection of anti-CD40 IgG prior to CD8+ T cell injection achieved comparable levels of T-cell accumulation, CPT elimination, and significantly extended survival in the absence of radiation treatment.However, lower T cell accumulation and higher rates of tumor recurrence were reported [153] .

Heat-shock protein and oncometabolism-
Recent evidence has highlighted the potential antitumoral activity of heat-shock protein 70 (Hsp70), a molecular chaperone.Hsp70 has the ability to deliver tumor-associated peptides to antigen-presenting cells for subsequent presentation of these antigens via major histocompatibility class I to CD8 + T-lymphocytes, thereby inducing a tumor-specific immune response [154] .Shevtsov et al. conducted a study utilizing immunomodulation via recombinant Hsp70 in the treatment of malignant brain tumors in pediatric patients, one of whom had choroid plexus carcinoma and had only a partial response to treatment with delayed-type hypersensitivity [155] .Furthermore, heat-shock protein inhibition has shown the potential to overcome thermoresistance during PTT [111] .Further investigation is warranted to apply this technology to CPTs.Due to their highly vascularized nature; these tumors are theoretically well-suited for an immune cell-mediated approach.
Another novel approach to manipulate TME is oncometabolism, which aims to modify the local metabolic activity to restrict the growth or induce the destruction of tumors.To the best of our knowledge, no clinical trials have been conducted to treat CPTs using oncometabolism approach.However, there are several ongoing or completed clinical trials investigating the use of oncometabolism in the treatment of other malignant brain tumors [156] .

CPT biomarkers-Precision immunotherapy requires sensitive and specific
biomarkers for each tumor group and subgroup.Some promising biomarkers have been identified as diagnostic and therapeutic targets for CPTs.Kir7.1, an inward rectifier potassium channel, and stanniocalcin-1, a homodimeric glycoprotein, showed significant upregulation in CPTs compared to other brain tumors [6,157] .In distinguishing between CPT subtypes, higher aCPPs expressed significantly more S-100(+)/Vim(+)/Syn(+) compared to their regular counterpart [68] .In canine models, E-cadherin was expressed in all CPT grades, independent of tumor invasion.N-cadherin immunolabeling was expressed more in grade I than in high-grade CPTs, whereas doublecortin expression was not detected in CPTs [158] .Further investigation into these biomarkers is warranted to develop treatments and diagnostic approaches with superior specificity and efficacy.4.3.6.Gene therapy and epigenetic modulators-Gene therapy and epigenetic modulators offer another potential avenue in the treatment of CPTs.Although current and past clinical trials have yet to include patients with CPTs, there are several trials focusing on using virotherapy to treat brain tumors.Notably, the trial NCT04105374 is investigating the addition of anticancer viral gene therapy using Toca 511 and Toca FC for newly diagnosed glioblastomas [159] .Virotherapy has also been explored for pediatric brain tumors, using herpes simplex virus (G207), reovirus (pelareorep/Reolysin), measles virus (MV-NIS), poliovirus (PVSRIPO), and adenovirus (DNX-2401, AloCELYVIR) to treat gliomas and meduloblastomas [160,161] .Another approach to gene therapy involves the therapeutic use of microRNA (miRNA).In glioblastoma, miRNAs play a major role in the transcriptional control, growth, and proliferation of numerous tumor genes, in addition to performing a number of important roles in carcinogenesis, the expression of cancer-related genes, glioma stem cell development, and regulatory pathways [162][163][164][165][166] .Furthermore, chromatin remodeling, another method with therapeutic potential in gliomas, may also find future applications in treating CPTs [167][168][169] .While no clinical trials have been conducted specifically for treating CPTs, a growing body of literature reports target genes and epigenetic mechanisms specific to choroid neoplasms, paving the way for more tailored treatments, diagnostic indicators, and prognostic indicators in the future.
Several chromosomal imbalances have been reported in association with CPTs.These chromosomal imbalances play a factor in as much as 94% of CPPs and 100% of CPCs, according to Rickert et al. [170] .de Oliveira Garcia et al. reported gains on chromosomes 12, 18, and 20, as well as copy-number losses on chromosomes 13q and 22q (BRD1 locus) in an aCPP [171] .Yankelevich et al. analyzed the molecular changes in the malignant transformation of a CPP into carcinoma and found significant aneuploidy with mostly gains present in the papilloma and significant loss in chromosome 13 (which included the loss of tumor suppressor genes RB1 and BRCA2) [35] .Thomas et al. found that copy-number alterations mainly represented whole-chromosomal alterations with subgroupspecific enrichments (gains of chromosomes 1, 2, and 21q in the "pediatric B" group and gains of chromosomes 5 and 9 and loss of chromosome 21q in the "adult" group) [172] .Among the frequently reported genome defects were germline TP53 mutations or Li-Fraumeni syndrome, which tend to be associated with a poorer prognosis and poor response to radiation therapy [34,35,171,173] .Epigenetic profiling of CPTs can be used for the identification of patients at risk of recurrence and is expected to play a role in treatment stratification and patient management in future clinical trials.Several studies have explored the methylation patterns that characterize CPTs, distinguishing the three subtypes from one another and categorizing them based on aggressiveness [174][175][176] .In a more recent comprehensive review, Thomas et al.
used DNA methylation profiling to classify CPTs into three distinct epigenetic subgroups: supratentorial pediatric low-risk CPTs (CPP and aCPP), infratentorial adult low-risk CPTs (CPP and aCPP), and supratentorial pediatric high-risk CPTs (CPP and aCPP and CPC) [174] .Once a complete picture of CPT epigenetic traits is obtained, DNA methylation inhibitors, histone deacetylase inhibitors, and other such regulators can be administered, as this approach has shown some modest success in some studies [177,178] .4.3.7.Nanomedicine-Nanomedicine, an umbrella term encompassing all technologies on the nanoscale, has made significant progress within the realm of oncology in recent years.Although clinical literature on nanomedicine's direct application to CPTs is scarce, a growing body of research demonstrates its potential in the treatment of tumors.Emerging nanomedicine approaches have been used to enhance chemotherapy, phototherapy, immunotherapy, and gene therapy, with several of these technologies currently under evaluation in clinical trials [125,[179][180][181][182][183] .Nanomedicine also holds considerable promise in emerging drug delivery mechanisms, such as carrier-free nanomedicines.These nanomedicine exhibit longer blood half-life, better tumor selectivity, enhanced tumor accumulation, and significantly improved antitumor efficacy compared to free drugs, as demonstrated in vivo studies [184][185][186] .It is only a matter of time before these emerging technologies find their way into neuro-oncology, as there is already speculation about their possible role in the treatment of CNS disorders [187] .

Conclusion
CPTs can be difficult to distinguish due to the similar pathophysiology shared by the tumor subtypes, which result in overlapping manifestations.However, CPT subtypes can be clearly differentiated from each other by detecting differences in histology, immunohistochemistry, imaging, gross appearance, location, metastatic behavior, treatment approach, and prognosis.Therefore, a better understanding of these differences can aid in exploring future treatments for CPTs.Emerging treatments for CPTs include neuroendoscopy, LITT, PTT, immunotherapy, manipulation of the TME, gene therapy, epigenetic modulators, and nanotechnology.However, CPTs mainly affect pediatric patients, often presenting as small, highly vascularized tumors.These factors, in addition to their relatively lower incidence rate, complicate their management using conventional techniques as well as novel treatments, many of which are primarily focused on more common brain tumors.Further investigation is warranted to establish a standard treatment approach for each CPT subtype and the applicability and efficacy of emerging treatments.Axial non-contrast computed tomography of a choroid plexus carcinoma.Source: MedPix ® (Smirniotopoulos JG, 2009), https://medpix.nlm.nih.gov/case?id=2ae2b1c4-9029-4535-8f1b-a12a8c9e3a8f.ii.
Ventricular enlargement may not be present.
iii.Perfusion MRI will typically reveal increased cerebral perfusion.

i.
Prenatal ultrasound and neurosonogram through an unfused anterior fontanelle will demonstrate echogenic lesions with bidirectional flow in the ventricles throughout diastole. ii.
CT demonstrates ventriculomegaly with hyper-to isodense lobulated lesions with slightly irregular margins within the ventricles.

iii.
Calcifications can be observed in about 25% of patients.

iv.
MRI demonstrates flow voids and enhanced well-defined intraventricular lesions.

i.
CT and MRI scan findings similar to those seen in CPPs.
ii. MRI findings in more likely to show cysts, necrotic changes, peritumoral edema, unclear tumor boundaries, and greater volume masses. iii.

Table 1 .
Comparative summary of the different choroid plexus tumors